4-alkylpyrazoles



4-ALKYLPYRAZOLES George Karmas, Somerville, N.J., assignor to Orthogharmaceutical Corporation, a corporation of New ersey No Drawing.Application April 16, 1958 Serial No. 728,769

6 Claims. (Cl. 260-310) in which R is selected from the group consistingof hydrogen and methyl radicals and R is an alkyl radical selected fromthe group consisting of heptyl, octyl, nonyl and decyl radicals; and toa process for making these compounds. These novel compounds haveanticonvulsant properties and are useful in the treatment of epilepsy.

Epilepsy has been defined as a cerebral dysrhythmia which may or may notbe accompanied by lossof consciousness and body movements. It is nowknown that epileptic convulsions are related to the flow of electricityfrom neurons of the cerebral cortex. The type of chemical reaction whichis responsible for these cerebral neuronal discharges is not known, butgenerally, convulsions and loss of consciousness are characterized byabnormally fast brain Waves. When the patient suffers loss ofconsciousness and convulsions, the seizures are referred to as'grandmal, a form of major epilepsy. However, convulsions do not necessarilyaccompany epilepsy, and in some instances consciousness is not lost.When the patient loses consciousness but convulsions are not observed,the attacks are known as petit mal. A third type of epilepsy has beenclinicially classified as psychomotor epilepsy.

Many drugs are known which reduce or diminish epileptic seizures-in man.In general, those drugs which will act as depressants of nervoustransmission are eiiective for this purpose. The hypnotics, such as thebarbiturates, are effective in doses sufficient to produce anesthesia.Phenobarbital is one of the better anticonvulsants, but must beadministered in hypnotic doses. The related hydantoins and.oxazolidinediones have also been found to possess anticonvulsantproperties. Such drugs, however interfere to a greater or lesser extentwith the normal activities of the patient. I

It is most important, that any drug which is used as an anticonvulsanthave very low toxicity since the nature of epilepsy requires that thepatient use the drug daily and over a long period of time. The idealanticonvulsant drug should be non-toxic, Well tolerated, long acting,and devoid of sedative effects.

It isa purpose of this invention to'provide a method of reducing oreliminating convulsions in animals and in man by administeringanticonvulsant compositions. Our new compositions are useful forveterinary purposes. Effectiveness has been found fora variety ofanimals, including dogs, mice, rats and monkeys. T

I 2,931,814 Patented Apr. 5, 196,0

It is also an object of this invention to provide an efiicient methodfor making 4-alkylpyrazoles.

Still another object of this invention is to provide 4- alkylpyrazolecompositions for use in the treatment of epilepsy.

It has been found that the aforesaid pyrazoles have unexpected andunobvious properties of great value in combating epilepsy. Thesecompositions may take the form of tablets, powders, capsules, or otherdosage forms which will be particularly useful for oral ingestion. Thecompositions may take the form of active materials, namely the4-alkylpyrazoles, admixed with solid diluents and/or tablettingadjuvants such as corn starch, sucrose, lactose, magnesium stearate,talc, aluminum hydroxide, calcium carbonate gums such as acacia, or thelike. Any of the tabletting materials used in pharmaceutical practicemay be employed where there is no incompatibility with the4-alkylpyrazoles. The material may be placed in a gelatin capsule andadministered in that form. Alternatively, the 4-alkylpyrazole may beemulsified in a liquid in which the 4-alkylpyrazole is not soluble.

It has been found that only certain members of the 4-alkylpyrazoleseries have great value in combating epilepsy. Insofar as is known, thephysiological properties of 4-alkylpyrazoles have notheretofore beeninvestigated; nor have any of these compounds been applied fortherapeutic purposes.

Anticonvulsant drugs may be assayed in the laboratory by the minimumelectro-shock method. In this procedure, the drug is administered orallyto the animals under test. After one hour, the animal is subjected to adirect-current stimulus that is approximately equal to three times thecurrent necessary to produce maximum seizures. The effectiveness ofvarious 4-alkylpyrazoles as anticonvulsants is summarized in the table.In this table, the first column gives the efiective dose in milligramsper kilogram required to prevent convulsions in one-half of theanimalssubjected to the minimum electro-shock procedure. The second columnindicates the amountof drug in milligrams per kilogram that producedneurological toxic symptoms in one-half of the experimental group. Thethird column of this table reports the amount of drug, again inmilligrams per kilogram, that was fatal to fifty percent of the testgroup. Column four indicates the protective index ('N.T.D. -:E.D. andthe fifth column gives the therapeutic index (L.D. -:-E.D.

Substituted ED NID LD PI TI Pyrazoles 75-125 125-250 500 1. 3 4 -75250-500 250-500 3. 3-6.7 3. 3 50 50-75 500-750 1-1. 5 10-15 4-Octvl50-75 75-125 750-1, 000 1-2. 5 10-15 4-Octvl-3- methvl 50-75 125-250 5001.7-5 ca. 10 4-N'0n"l 50-75 200-250 750-1, 000 3-5 10- 13 4-Decyl 75 7502, 000-2, 500 10 26-33 4-Dec l-3- methvL. 75-125 75-125 250-500 0 5-22-4 l-Undec l w 1, O00 4-Dodecyl. y 1, 000 4-Hexadecyl m 1, O00 4-Pheny1-500 500-1, 000 4-P henvl-3- methyl 0 at 250 250-500 500 4-Benzyl 75-100125-250 500-750 1 2-3.3 5-7. 5

The 4-alky1pyrazoles have been prepared by the following reactions:

a 110.0 g on. -CH:

N T N N N (B) on. on. on. NgH

None of these syntheses is suitable for pyrazoles with the alkyl grouplarger than methyl because of the inaccessibility of the necessaryhomologous starting materials.

The 4-alkylpyrazole of the present invention may be obtained by thefollowing sequence of reaction steps:

H CEO I N2 4 RCHaC O2C: s RCHC 0262 5 N R v R Reduction N p N N 01 POClaThe reduction of the 4-alkyl-5-chloropyrazole with hydrogen andpalladium to give the corresponding 4-alkylpyrazole is very troublesomerequiring frequent additions of fresh catalyst and a reduction period ofseveral days. A superior reduction process consists of the reaction of-chloropyrazoles with sodium in liquid ammonia, an easily-performedprocedure which always gives very high yields of the dechlorinatedpyrazoles.

EXAMPLE I.--4-HEPTYLPYRAZOLE 4-heptylpyrazOl0ne-5 A suspension of sodiumbutoxide is prepared by vigorously stirring and refluxing a mixture of25.3 grams (1.10 moles) of sodium, 145 milliliters of dry n-butanol and1000 milliliters of toluene until evolution of hydrogen has ceased. Thissuspension is chilled to 5 C., 100 milliliters of dry ethyl formate isadded and the mixture is stirred for ten minutes in the cold and then200 grams (1.074 moles) of ethyl pelargonate is added. The for mylationmixture is allowed to stand at 25 C., for 48 4 hours and then it is keptat 0 C. to 5 C., and stirred while 400 milliliters of ice water isadded. The layers are separated and the toluene solution is extractedwith milliliters more water and then the combined aqueous solution isstirred with 300 milliliters of ether and chilled in ice while a mixtureof 100 milliliters of concentrated hydrochloric acid and 100 grams ofchopped ice is added rapidly to liberate the free formyl ester from. itswater-soluble sodium salt. After separation of layers, the aqueous phaseis extracted again, with 200 milliliters of ether, and the combinedether solution is concentrated at room temperature, under waterpumpvacuum, to a volume of 300 milliliters of methanol, 85 milliliters of85% hydrazine hydrate is added, and the mixture is refluxed for twohours and then concentrated under vacuum to a solid residue of thepyrazolone. Recrystallization of the crude solid from ethanol gives 72.7grams (37%) of 4-heptylpyrazolone-5, fine white prisms which melt at159-160 C.

Analysis.Calcd. for C H N OZ N, 15.37. Found: N, 15.55.

4-heptyl-S-chloropyrazole A mixture of 20 grams (0.11 mole) of4-heptylpyrazolone-S and 55 milliliters of phosphorus oxvchloride isheated in a sealed tube at 180 C., for fifteen hours. After cooling, thetube contents are concentrated under vacuum to remove excess oxychlorideand the residue is hydrolyzed on ice. The chloropyrazole is extractedwith methylene dichloride after the hydrolysis mixture has beenneutralized with aqueous ammonia and then the combined extracts aredried with magnesium sulfate and concentrated. Distillation of theresidual oil gives 11.9 grams (54%) of 4-heptyl-5-chloropyrazole, aclear oil which boils at -116 C. (1.0 micron) and has n Analysis.Calcd.for C H N CI: C, 59.87; H, 8.54. Found: C, 59.55; H, 8.54.

4-heptylpyrazo le A solution of 10.0 grams (0.05 mole) of 4-heptyl-5-chloropyrazole in 35 milliliters of dry ether is added with stirring to200 milliliters of liquid ammonia. To this stirred solution is addedsmall pieces of sodium metal until a deep blue color persists, at whichpoint the reduction is complete. Then 6 grams of ammonium chloride iscautiously added and the excess ammonia is allowed to evaporate. Fiftymilliliters of water and 100 milliliters of ether are added to theresidue and, after shaking, the layers are separated and the aqueouslayer is again extracted with 100 milliliters of ether. The combinedother solution is dried with magnesium sulfate and concentrated.Distillation of the residual oil gives 8.0 grams (96%) of4-heptylpyrazole, a colorless solid which melts at 28-30 C., and boilsat 95-97 C. (0.05 mm.).

Analysis.--Calcd. for C H N- z C, 72.23; H, 10.92. Found: C, 72.34; H,11.09.

EXAMPLE lI.-4-OCTYLPYRAZOLE 4-0ctylpyraz0l0ne-5 Crude ethyla-formyldecanoate is prepared exactly as described in Example I,4-heptylpyrazolone-5, using 24 grams of sodium, milliliters of butanol,1200 milliliters of toluene, 90 milliliters of ethyl formate and 200grams (1.0 mole) of ethyl decanoate. The formyl ester is then condensedwith 80 milliliters of 85% hydrazine hydrate as described in Example I,4-heptylpyrazolone-5. The crude solid obtained on evaporation of themethanol solution is recrystallized from 400 milliliters of ethanol togive 69.7 grams (35.5%) of 4-octylpyrazolone-5, white prisms which meltat 151-153" C.

Analysis.Calcd. for C H N O: N, 14.27. Found: N, 13.79.

4-octyl-5-chlor0pyrazole Twenty grams (0.10 mole) of 4-octylpyrazolone-5is reacted with 55 milliliters of phosphorus oxychloride exactly asdescribed in Example I, 4-heptyl-5-chloropyr-' azole. After an identicalworking-up of the reaction mixture, distillation afiords 12.6 grams(58%) of 4- octyl-5-chloropyrazole, a colorless oil which boilsat 120-122 C. (1.0 micron) and has n 1.4881.

Analysis.-Calcd. for C H N Cl: C, 61.58; H, 8.92. Found: C, 61.76; H,9.03.

The reduction of 11.9 grams (0.055 mole) of 4-octyl- 5-chloropyrazolewith sodium in liquid ammonia is performed and worked up exactly asdescribed in Example I, 4-heptylpyrazole. Distillation of the productgives 9.6 grams (96%) of 4-octylpyrazole, a colorless solid which boilsat 112-114 C. (0.05 mm.) and melts at 51-52 C.

Analysis.-Calcd. for C H N C, 73.28; H, 11.18. Found: C, 73.11; H,11.30.

EXAMPLE III.4-NONYLPYRAZOLE 4-nonylpyrazoLone-5 Crude ethylu-formylundecylate is prepared exactly as described in Example I,4-heptylpyrazolone-5, using 11.3 grams of sodium, 60 milliliters ofbutanol, 500 milliliters of toluene, 45 milliliters of ethyl formate and100 grams (0.467 mole) of ethyl undecylate. The formyl ester is thencondensed with 35 milliliters of 85% hydrazine hydrate as described inExample I, 4-heptylpyrazolone-5. The crude solid obtained on evaporationof the methanol solution is recrystallized from 270 milliliters ofethanol to give 28.5 grams (29%) of 4-nonylpyrazolone-5, white prismswhich melt at 156-157 C.

Analysisr Calcd. for C H N O: N, 13.32. Found: N, 12.96. v

4-nonyl-5-chloropyrazole Thirteen grams (0.062 mole) of4-nonylpyrazolone-5 is reacted with 50 milliliters of phosphorusoxychloride exactly as described in Example I,4-heptyl-5-chloropyrazole. After an identical working-up of the reactionmixture, distillation affords 9.0 grams (64%) of 4-nonyl-S-chloropyrazole, a colorless oil which boils at 117-120 C. (1.0 micron)and has n 1.4879.

Analysis.Calcd. for C H N Cl: C, 63.00; H, 9.25. Found: C, 63.07; H,9.53.

The reduction of 9.0 grams (0.039 mole) of 4-nonyl- 5-chloropyrazolewith sodium in liquid ammonia is performed and worked up exactly asdescribed in Example I, 4-heptylpyrazole. Distillation of the productgives 7.5 grams (95%) of 4-nonylpyrazole, a colorless solid which boilsat 105107 C. (5 microns) and melts at 4849" C.

Analysis.-Calcd. for C H N C, 74.17; H, 11.42. Found: C, 74.86; H,11.55.

EXAMPLE IV.4-DECYLPYRAZOLE 4-decylpyrazolone-5 i-decyl-S-chlorbpyrazoleThirteen grams (0.058 mole) of 4-decylpyrazoloneis reacted with 50milliliters of phosphorus oxychloride exactly as described in Example I,4-heptyl-5-chloropyrazole. After an identical working-up of the reactionmixture, distillation affords 7.9 grams (56%) of 4-decyl-5-chloropyrazole, a colorless oil which boils at 132-135 C. 1.0 micron)and has n 1.4865.

Analysis.-.Calcd. for C H N Cl: C, 64.27; H, 9.55. Found: C, 64.69; H,9.54.

4-decylpyraz0le The reduction of 7.9 grams (0.0325 mole) of 4-decyl-5-chloropyrazole with sodium in liquid ammonia is performed and workedup exactly as described in Example I, 4-heptylpyrazole. Distillation ofthe product affords 6.7 grams (98%) of 4-decylpyrazole, a colorlesssolid which boils at 116118 C. (0.05 mm.) and melts at 6364 C.

Analysis.-Calcd. for C H N C, 74.98; H, 11.61. Found: C, 74.93; H,11.61.

EXAMPLE V.-3-METHYL-4-OCTYLPYRAZOLE Seven grams (0.305 mole) of sodiumis dissolved in 230 milliliters of anhydrous ethanol and the resultingsolution of sodium ethoxide is stirred at 5 C., While a mixture of 61.8milliliters (0.30 mole) of methyl nonyl ketone and 29 milliliters ofethyl formate is added within a period of thirty minutes. Thisformylation mixture is allowed to stand at 25 C., for sixteen hours andthen it is concentrated at 30-35 C., under vacuum until most of thealcohol has been removed. The residue is shaken with 200 milliliters ofpentane and 150 milliliters of icewater to extract the sodium' salt ofthe formylketone, and then the latter is liberated by acidification ofthe aqueous phase with hydrochloric acid and extraction with 300milliliters ether. The ether extract is washed with two small portionsof water, dried with magnesium sulfate and concentrated under vacuum.The crude 3-formyiundecanone-Z thus obtained is purified by distillingit three times through a six-inch Vigreux column, collecting the desiredmaterial at 9394 C. (1.0 mm.). This proc ess of repeated distillationdestroys by polymerization the less stable isomericl-formyl-undecanone-Z and affords the desired 3-formyl ketone as a whitesolid which is recrystallized from 30 milliliters of pentane to give16.2 grams (27%) of fine white granules which melt at 43- 44" C.Analysis.Calcd. for C H O C, 72.67; H, 11.1.8. Found: C, 72.54; H,11.32. To a solution of 13.1 grams (0.066 mole) of 3-formylundecanone-Zin 150 milliliters of ethanol is added 4.5

milliliters of hydrazine hydrate and the mixture is refluxed for twohours and then concentrated under vacuum. The residual oil is dissolvedin 200 milliliters of pentane and this solution is dried with magnesiumsulfate and then concentrated and the crude product isdistilled toafiord 3-methyl-4-octylpyrazole as a colorless oil which distills at102-103 C. (5 microns), and has 11 1.4812. The yield is 12.3 grams(96%). Analysis.-Calcd. for C H N C, 74.18; H, 11.41. Found: C, 74.64;H, 11.66. v

The percentage of 4-alkylpyrazole in a pharmaceutical composition forthe treatment of epilepsy may be varied. It is necessary that the activeingredient constitute a portion such that suitable dosage will beobtained. Obviously, several dosage unit forms may be administered atabout the same time. Although a percentage less than 0.1% of activeingredient is eflective, it is preferred to use not less than 0.1% ofactive agent. The percentage of active agent may be conveniently 10% or25% or even 50% since activity increases with the concentration ofactive material. Tablets containing from about 25 to about 50 mg. of the4-alkylpyrazole are particularly useful. The following formulations areintended to be illus trative only, and may be varied or modified to aconsiderable extent without departing from the spirit of the invention.I do not, therefore, intend to limit this invention to the Specificembodiments herein set forth.

EXAMPLE VI G. Calcium carbonate 0.500 4-decylpyrazole 0.005 Calciumstearate 0.050

The 4-decylpyrazole is adsorbed onto of the calcium carbonate by mixing.The remaining calcium carbonate, previously granulated with water anddried, is added to this pyrazole mixture. The calcium stearate is thenadded and after mixing until uniform, the mixture is compressed intotablets.

EXAMPLE VII G. Aluminum hydroxide 0.300 Sucrose 0.100 Lactose 0.100Gelatin solution 0.005 3-methyl-4-octylpyrazole 0.050 Magnesium stearate0.005

The 3methyll-octylpyrazole is adsorbed onto 10% of the aluminumhydroxide with mixing. The remainder of the aluminum hydroxide is thengranulated with the sucrose, lactose, and gelatin solution and dried at50 C. These granules are then mixed with the pyrazole-aluminum hydroxidecomposition and magnesium stearate until uniform and compressed intotablets. 7

EXAMPLE VIII G. Calcium carbonate 0.250 Lactose 0.250 Acacia solution0.005 4-nonylpyrazole 0.050 Magnesium stearate 0.005

The 4-nonylpyrazole is adsorbed onto 10% of the calcium carbonate withmixing. The remainder of the calcium carbonate is granulated with thelactose and acacia solution and dried at 50 C. These granules are thenadded with the calcium carbonate-pyrazole mixture and The4-octylpyrazole is adsorbed onto 10% of the magnesium trisilicate bymixing. The remainder of the trisilicate is granulated with the lactoseand sodium alginate solution and dried at 50 C. To these granules isadded the 4-octylpyrazole adsorbed on magnesium trisilicate and themagnesium stearate. These ingredients are mixed until uniform andcompressed into tablets.

8 EXAMPLE X G. Aluminum hydroxide 0.300 Sucrose, powdered 0.100 Lactose,powdered 0.100 4-heptylpyrazole 0.050 Magnesium stearate 0.005

The 4-hep'tylpyrazole is adsorbed onto 10% of the aluminum hydroxidewith mixing. The remainder of the aluminum hydroxide, together with thesucrose and lactose, is then added and the composition mixed untiluniform. The magnesium stearate is then added with additional mixing andthe product is filled into hard gelatin capsules.

While the invention has been described with particular reference tospecific embodiments, it is to be understood that it is not to belimited thereto but is to be construed broadly and restricted solely bythe scope of the appended claims.

What is claimed is:

1. The compound 4-.n-heptylpyrazo1e.

2. The compound 4-n-octylpyrazole.

3. The compound 4-n-nonylpyrazole.

4. The compound 4-n-decylpyrazole.

5. The compound 3-methyl-4-n-0ctylpyrazole.

6. A process for the preparation of a compound having the formula inwhich R is a member of the group consisting of hydrogen and methylradicals and R is a straight'chain alkyl radical selected from the groupconsisting of heptyl, octyl, nonyl and decyl radicals which comprisesreducing a compound having the formula in which R and R have the meaningdefined above, with metallic sodium in the presence of liquid ammonia.

References Cited in the file of this patent UNITED STATES PATENTS2,725,384 Burness Nov. 29, 1955 FOREIGN PATENTS 520,855 Germany Mar. 19,1931 OTHER REFERENCES MacArdle: Use of Solvents (Van Nostrand), p. 33(1925).

Parham et al.: J. Am. Chem. Soc., Vol.72, pp. 3843-6 1950) Pino et al.;Chem. Abstracts, vol. 46, col. 7042 (1952).

Houben: Die Methoden der Org. Chem, vol. 2, pp. 355-363 (1943)(Photo-Lithoprint by Edwards Brothers, Inc.).

1. THE COMPOUND 4-N-HEPTYLPYRAZOLE.
 2. THE COMPOUND 4-N-OCTYLPYRAZOLE.
 3. THE COMPOUND 4-N-NONYLPYRAZOLE.
 4. THE COMPOUND 4-N-DECYLPYRAZOLE.
 5. THE COMPOUND 3-METHYL-4-N-OCTYLPYRAZOLE. 